Digestion constitutes the physiological process by which ingested food is broken down into readily absorbed nutrient components. Following ingestion, food passes through various segments of the gastrointestinal tract and digestion is carried out, primarily by digestive enzymes. Three groups of digestive enzymes essential to this process include lipases (for fat digestion), proteases (for protein digestion) and amylases (for carbohydrate digestion).
Food digestion and nutrient absorption occur in the small intestine. There, ingested food is broken down by digestive enzymes for ready absorption. Most digestive enzymes are secreted by the pancreas and arrive in the small intestine through the pancreatic duct.
The pancreas effects a variety of exocrine and endocrine actions required for proper digestion, nutrition and metabolism. Pancreatic exocrine activities include the secretion of proteins that function as enzymes in the small intestine to catalyze the hydrolysis of fat into glycerol and fatty acids, protein into peptides and amino acids and carbohydrates into dextrins, disaccharides and monosaccharides, such as glucose. Exocrine pancreatic insufficiency (hereinafter “pancreatic insufficiency”) results from a reduction in pancreatic function and can be caused by a number of clinical disorders. For example, pancreatic insufficiency is associated with cystic fibrosis, chronic pancreatitis, acute pancreatitis, pancreatic cancer and Shwachmann-Diamond Syndrome [E. P. DiMagno et al., in The Pancreas: Biology, Pathobiology and Disease, 2d Ed., V. Liang et al., eds., pp. 665-701 (1993)].
In patients afflicted with pancreatic insufficiency, the pancreas fails to produce and/or secrete sufficient amounts of digestive enzymes to support normal digestive processes, including digestion of fats, proteins and carbohydrates. As a result, those patients suffer from malabsorption of nutrients. Clinical manifestations of pancreatic insufficiency include abdominal cramping, bloating, diarrhea, steatorrhea, nausea and weight loss.
Pancreatic insufficiency is present in 89% of patients suffering from cystic fibrosis [D. Borowitz et al., “Use of Fecal Elastase-1 to Identify Misclassification of Functional Pancreatic Status in Patients with Cystic Fibrosis”, J. Pediatr., 145, pp. 322-326 (2004)]. Cystic fibrosis is an autosomal recessive genetic disorder that primarily affects the gastrointestinal and respiratory systems [S. M. Rowe et al., “Mechanisms of Disease: Cystic Fibrosis”, N. Engl. J. Med., 352, pp. 1992-2001 (1995)]. Abnormal amounts and viscosity of mucus produced in cystic fibrosis patients impede the secretion of sufficient amounts of pancreatic enzymes. The decreased volume of pancreatic secretions leads to inspissation within the pancreatic ducts, preventing egress of enzymes and bicarbonate into the duodenum. As a result, cystic fibrosis patients with pancreatic insufficiency suffer from impaired digestion and experience significant malabsorption of fat and protein. For example, such patients typically absorb less than 60% of dietary fat [M. Kraisinger et al., “Clinical Pharmacology of Pancreatic Enzymes in Patients with Cystic Fibrosis and in vitro Performance of Microencapsulated Formulations”, J. Clin. Pharmacol., 34, pp. 158-166 (1994)]. If left untreated, maldigestion and malabsorption in cystic fibrosis patients lead to malnutrition, inability to gain or maintain weight and decreased growth, as well as worsening of chronic suppurative lung disease [K. Gaskin et al., “Improved Respiratory Prognosis in CF Patients with Normal Fat Absorption”, J. Pediatr., 100, pp. 857-862 (1982); J. M. Littlewood et al., “Control of Malabsorption in Cystic Fibrosis”, Paediatr. Drugs, 2, pp. 205-222 (2000)].
To date, standard therapy for pancreatic insufficiency is primarily based on orally-administered porcine pancrelipase, containing a mixture of lipases, trypsin, chymotrypsin, elastase and amylases. Although porcine pancreatic enzyme supplements contain substantial amounts of amylase, it has been reported that cystic fibrosis patients have normal amylase levels [P. L. Townes et al., “Amylase Polymorphism: Studies of Sera and Duodenal Aspirates in Normal Individuals and in Cystic Fibrosis”, Am. J. Hum. Genet., 28, pp. 378-389 (1976)]. Accordingly, it is believed that amylase serves no function in increasing polysaccharide digestion [E. Lebenthal et al., “Enzyme Therapy for Pancreatic Insufficiency: Present Status and Future Needs,” Pancreas, 9, pp. 1-12 (1994)]. The lipase, protease and amylase components of porcine pancreatic supplements are typically present in a 1:3.5:3.5 ratio.
Pancreatic enzyme supplements are normally administered orally with meals. As these supplements pass through the low pH environment of the stomach, their enzyme activity diminishes rapidly. As a result, large quantities of enzyme concentrate (sometimes as many as 15 capsules or tablets per meal) have been required to ensure that sufficient active enzyme is present in the proximal intestine to relieve pancreatic insufficiency.
Because protease and lipase can become irreversibly inactivated in the stomach's acidic environment, enteric-coating technologies have been applied to pancrelipase products, to enclose enzymes in microbeads or otherwise treat them with a protective enteric coating. While such enteric-coatings improved the product profile, large quantities of supplements were still required to yield therapeutic benefit [J. H. Meyer, in Pancreatic Enzymes in Health and Disease, P. G. Lankisch, ed., pp. 71-88 (1991)]. A high-strength pancrelipase product line (Ultrase®) was introduced, with the goal of reducing the quantities of tablets or capsules necessary to treat pancreatic insufficiency. However, in 1991 the United States Cystic Fibrosis Foundation, in conjunction with the FDA, reported multiple cases of fibrosing colonopathy in children with cystic fibrosis taking such high-strength products [S. C. Fitzsimmons et al., “High-Dose Pancreatic-Enzyme Supplements and Fibrosing Colonopathy in Children with Cystic Fibrosis”, N. Engl. J. Med., 336, pp. 1283-1289 (1997)]. In these patients, colonic fibrosis caused strictures that often required surgery and, in some cases, colectomy.
As a means toward reducing daily doses of pancreatic enzymes, the FDA removed the high strength products (defined as greater than 2,500 USP units per kg body weight) from the market [D. S. Borowitz et al., “Use of Pancreatic Enzyme Supplements for Patients with Cystic Fibrosis in the Context of Fibrosing Colonopathy”, J. Pediatr., 127, pp. 681-684 (1995)]. In addition, the United States Cystic Fibrosis Foundation, jointly with the FDA, recommended a detailed examination of the complex nature of porcine enzyme extracts [Id.]. The Consensus Panel also recommended investigation of alternative, acid-stable lipases.
Whether or not a given pancreatic enzyme supplement is enterically-coated, the bioavailability of such supplements varies widely, due to differentials in acidification of the intestine among patients. As a result, many patients take pH altering drugs, such as histamine-2 (H2) receptor blockers and proton pump inhibitors (PPI), to improve the clinical efficacy of the enzyme supplements [P. G. Lankish, “Enzyme Treatment of Exocrine Pancreatic Insufficiency in Chronic Pancreatitis’, Digestion, 54 (Supp. 2), pp. 21-29 (1993); D. Y. Graham, “Pancreatic Enzyme Replacement: the Effect of Antacids or Cimetidine”, Dig. Dis. Sci., 27, pp. 485-490 (1982); J. H. Saunders et al., “Inhibition of Gastric Secretion in Treatment of Pancreatic Insufficiency”, Br. Med. J., 1, pp. 418-419 (1977); H. G. Heijerman et al., “Omeprazole Enhances the Efficacy of Pancreatin (Pancrease) in Cystic Fibrosis”, Ann. Inter. Med., 114, pp. 200-201 (1991); M. J. Bruno et al., “Comparative Effects of Adjuvant Cimetidine and Omprazole during Pancreatic Enzyme Replacement Therapy”, Dig. Dis. Sci., 39, pp. 988-992 (1994)].
Variability in terms of potency and pharmaceutical properties and lack of stability have also been identified as important factors contributing to a poor response of some patients to conventional pancreatic enzyme supplements [C. L. Chase et al., “Enzyme Content and Acid Stability of Enteric-Coated Pancreatic Enzyme Products in vitro”, Pancreas, 30, pp. 180-183 (2005); D. S. Borowitz et al., J. Pediatr., 127, supra; C. J. Powell et al., “Colonic Toxicity from Pancreatins: a Contemporary Safety Issue”, Lancet, 353, pp. 911-915 (1999); E. Lebenthal et al., “Enzyme Therapy for Pancreatic Insufficiency: Present Status and Future Needs”, Pancreas, 9, pp. 1-12 (1994); P. Regan et al., “Comparative Effects of Antacids, Cimetidine and Enteric Coating on the Therapeutic Response to Oral Enzymes in Severe Pancreatic Insufficiency”, N. Eng. J. Med., 297, pp. 854-858 (1977)]. These include batch-to-batch variation in enzyme activity, susceptibility to loss of activity over time by exposure to sunlight, heat or humidity and a poorly defined profile of adverse reactions [D. S. Borowitz et al., J. Pediatr., 127, supra]. Other factors that complicate pancreatic insufficiency therapy include destruction of the replacement enzymes by gastric juice and/or intraluminal proteases, asynchronous gastric emptying of enzyme supplement and meal nutrients, and delayed liberation of enzyme from enteric-coated preparations [P. G. Lankish, Digestion, 54 supra; P. Regan et al., N. Eng. J. Med., 297, supra].
Due to the problems of potency, stability and bioavailability characterizing conventional pancreatic enzyme supplements, the use of microbially-derived enzymes as alternatives to porcine-derived enzymes has been proposed. For example, U.S. Pat. No. 6,051,220 describes compositions comprising one or more acid stable lipases and one or more acid stable amylases, both preferably of fungal origin. United States patent application 2004/0057944 describes compositions comprising Rhizopus delemar lipase, Aspergillus melleus protease and Aspergillus oryzae amylase. United States patent application 2001/0046493 describes compositions comprising crosslinked crystalline bacterial lipase, together with a fungal or plant protease and a fungal or bacterial amylase.
Despite such developments, the need still exists for optimizing dosage formulations to further improve both the efficacy of pancreatic enzyme supplements and patient compliance. The goal of a pancreatic enzyme supplement displaying the highest efficacy at the lowest dose, and characterized by a well-defined safety profile, remains of great importance to all patients suffering from pancreatic insufficiency, including those in the cystic fibrosis community.